Bottom Line:
Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response.With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries.Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

ABSTRACTLarge-scale gene expression studies have mainly focused on highly expressed and 'discriminatory' genes to decipher key regulatory processes. Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response. Here we comprehensively analyzed the temporal oligonucleotide microarray data of lipopolysaccharide (LPS) stimulated macrophages in 4 genotypes; wildtype, Myeloid Differentiation factor 88 (MyD88) knockout (KO), TIR-domain-containing adapter-inducing interferon-beta (TRIF) KO and MyD88/TRIF double KO (DKO). Pearson correlations computed on the whole genome expression between different genotypes are extremely high (>0.98), indicating a strong co-regulation of the entire expression network. Further correlation analyses reveal genome-wide response is biphasic, i) acute-stochastic mode consisting of small number of sharply induced immune-related genes and ii) collective mode consisting of majority of weakly induced genes of diverse cellular processes which collectively adjust their expression level. Notably, temporal correlations of a small number of randomly selected genes from collective mode show scalability. Furthermore, in collective mode, the transition from large scatter in expression distributions for single ORFs to smooth linear lines emerges as an organizing principle when grouping of 50 ORFs and above. With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries. Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

Mentions:
The whole genome auto-correlation of all genotypes shows progressive response, correspondent to a progressive displacement of correlation from unity, to LPS stimulation using RMA normalized data (Figure 3A and Methods). We further checked the consistency of this result using another normalization process, MAS5 data (Figure S1A). Wildtype response follows distinctly different trend from MyD88 KO, TRIF KO and DKO that in turn are remarkably similar to each other. These results show i) 1% of auto-correlations variability is sufficient to discriminate different genotypes, and ii) the similar global gene expression behavior between single KOs and DKO suggests DKO possesses LPS response, too (see also section ‘Emergence of regulatory signature from scattered expressions in all genotypes’ for further proof of DKO response).

Mentions:
The whole genome auto-correlation of all genotypes shows progressive response, correspondent to a progressive displacement of correlation from unity, to LPS stimulation using RMA normalized data (Figure 3A and Methods). We further checked the consistency of this result using another normalization process, MAS5 data (Figure S1A). Wildtype response follows distinctly different trend from MyD88 KO, TRIF KO and DKO that in turn are remarkably similar to each other. These results show i) 1% of auto-correlations variability is sufficient to discriminate different genotypes, and ii) the similar global gene expression behavior between single KOs and DKO suggests DKO possesses LPS response, too (see also section ‘Emergence of regulatory signature from scattered expressions in all genotypes’ for further proof of DKO response).

Bottom Line:
Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response.With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries.Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

ABSTRACTLarge-scale gene expression studies have mainly focused on highly expressed and 'discriminatory' genes to decipher key regulatory processes. Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response. Here we comprehensively analyzed the temporal oligonucleotide microarray data of lipopolysaccharide (LPS) stimulated macrophages in 4 genotypes; wildtype, Myeloid Differentiation factor 88 (MyD88) knockout (KO), TIR-domain-containing adapter-inducing interferon-beta (TRIF) KO and MyD88/TRIF double KO (DKO). Pearson correlations computed on the whole genome expression between different genotypes are extremely high (>0.98), indicating a strong co-regulation of the entire expression network. Further correlation analyses reveal genome-wide response is biphasic, i) acute-stochastic mode consisting of small number of sharply induced immune-related genes and ii) collective mode consisting of majority of weakly induced genes of diverse cellular processes which collectively adjust their expression level. Notably, temporal correlations of a small number of randomly selected genes from collective mode show scalability. Furthermore, in collective mode, the transition from large scatter in expression distributions for single ORFs to smooth linear lines emerges as an organizing principle when grouping of 50 ORFs and above. With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries. Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.